权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Aminotrexate A Novel Strategy to Replace Methotrexate in Psoriasis

氨基氨蝶呤是替代甲氨蝶呤治疗银屑病的新策略

基本信息

批准号：
8020549
负责人：
JOHN A ZEBALA
金额：
$ 20.29万
依托单位：
SYNTRIX BIOSYSTEMS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-11 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8020549
关键词：
Academic Medical Centers Adherence Adverse effects Adverse event Affect Agitation Animals Antidotes Area Bioavailable Biological Availability Brain Caring Cells Chronic Chronic small plaque psoriasis Clinical Clinical Trials Data Dermatology Development Disease remission Disorientation Dose Double-Blind Method Effectiveness Enrollment Fatigue Folic Acid Folic Acid Antagonists Head Hepatotoxicity Hour Human Inflammatory Laboratories Leucovorin Licensing Memory Methods Methotrexate Neurocognitive Oral Oral Administration Patients Pharmaceutical Economics Pharmaceutical Preparations Phase Phase II Clinical Trials Phase III Clinical Trials Phototherapy Physicians Population Principal Investigator Psoriasis Quality of life Randomized Randomized Clinical Trials Reaction Relapse Relative (related person)Reporting Research Institute Safety Series Severities Small Business Innovation Research Grant Supplementation Symptoms Systemic Therapy Tablets Testing Texas Time Tissues Toxic effect Treatment Cost United States Variant active control comparative efficacy cost dosage experience follow-up indexing mental state neurotoxicity novel strategies phase 2 study phase 3 study programs response skin disorder standard of care

项目摘要

DESCRIPTION (provided by applicant): Aminotrexate(tm) (AMT) is an antifolate in the same class as MIX that we have established is nearly 100% orally bioavailable in humans with a lower interpatient coefficient of variation than MTX, and is much more rapidly taken up by cells and tissues. With regard to non-CNS toxicities and response to the antidote leucovorin, AMT is indistinguishable from MTX. Accordingly, we hypothesize (clinical hypothesis 1) that oral AMT will be efficacious in a greater maximum fraction of patients with moderate-to-severe psoriasis than oral MTX, and/or reach a particular level of symptom improvement quicker than after oral MTX. We have also discovered that at equipotent doses of AMT and MTX, human CSF and animal brain parenchyma accumulate significantly less AMT than MTX. As such, we also hypothesize (clinical hypothesis 2) that oral AMT will result in fewer patients with postdosing neurotoxicity, and/or patients experiencing less severe postdosing neurotoxicity. As a result, AMT may potentially be better tolerated, resulting in better long-term adherence to AMT compared to MTX. If a greater fraction of patients with respond to AMT than to MTX, and/or can be treated longer without becoming intolerant to the side-effects, AMT could have a major impact on the standard of care in psoriasis and would have critical pharmacoeconomic consequences by obviating cost-intensive biologic treatments. This SBIR Fast-Track proposal aims to test the above hypotheses by conducting a series of two sequential Phase 2/3 clinical trials. In the first Phase 2 dose-finding clinical trial to be conducted in SBIR Phase I (36 subjects, 12 weeks per subject, 6-12 month enrollment period), the Specific Aims will be to: (1): assess the safety of oral AMT in the treatment of moderate-to-severe plaque psoriasis; (2) establish the dose- response relationship of oral AMT in moderate-to-severe plaque psoriasis; and (3) determine if splitting the weekly dose over two tablets, given every 12 hours, is preferred over giving the fully weekly dose once, using PASI scoring and safety assessments. From the Phase 2 study results we will select the dose of oral AMT that results in maximum efficacy and best time-to-response while not resulting in treatment-emergent toxicities or intolerance. We will then carry this oral AMT dose forward into the Phase 3 double-blind, randomized clinical trial to be conducted in SBIR Phase II (390 subjects, 26 weeks per subject, 30-36 month enrollment period) to test AMT vs. MTX head-to-head via the following Specific Aims: (1) Compare the efficacy of oral AMT and oral MTX in the treatment of subjects with moderate-to-severe plaque psoriasis who have not previously received MTX; and (2) Compare the safety and tolerance of AMT with MTX by comparing adverse events and laboratory parameters, expanded with a specific assessment of neurocognitive and CNS related-side effects of both drugs. The primary efficacy end-point is improvement in area under the PASI-N curve at Week 26, where PASI-N is the mean percent reduction in the Psoriasis Area-and-Seve'rity Index (PASI). Secondary efficacy and neurocognitive end-points include: proportion of subjects achieving PASI 50 and PASI 75 at Week 10 and Week 26; time to PASI 75 (Kaplan Meier); physician Global Assessment (PGA); Dermatology Life Quality (DLQI), Psoriasis Symptom Assessment (PSA); and neurocognitive scores from MMSE, FAClT-Fatigue, and FACT/GOG-Ntx. At the conclusion of the Phase 2 and 3 clinical trials proposed herein, we aim to have the necessary efficacy and safety data required for a Product License Application (NDA,) to the FDA for the use of AMT in psoriasis.

描述（由申请人提供）：Aminotrexate(tm) （AMT）是一种与MIX属于同一类别的抗叶酸盐，我们已经确定其在人类中具有接近100%的口服生物利用度，患者间变异系数低于MTX，并且被细胞和组织吸收的速度更快。关于非中枢神经系统毒性和对解毒剂亚叶酸素的反应，AMT与MTX无法区分。因此，我们假设（临床假设1），与口服甲氨蝶呤相比，口服AMT对中重度牛皮癣患者的最大有效比例更高，并且/或者比口服甲氨蝶呤更快达到特定水平的症状改善。我们还发现，在等效剂量的AMT和MTX下，人类脑脊液和动物脑实质积累的AMT明显少于MTX。因此，我们也假设（临床假设2）口服AMT将导致较少的患者出现给药后神经毒性，和/或患者出现较轻的给药后神经毒性。因此，AMT可能具有更好的耐受性，与MTX相比，AMT的长期依从性更好。如果更多的患者对AMT有反应，而不是MTX，并且/或者可以更长时间地治疗而不会产生副作用，AMT可能对牛皮癣的护理标准产生重大影响，并通过避免成本高昂的生物治疗产生关键的药物经济学后果。这项SBIR快速通道提案旨在通过进行一系列2个连续的2/3期临床试验来验证上述假设。在SBIR I期进行的第一项2期剂量寻找临床试验（36名受试者，每个受试者12周，6-12个月的入组期）中，具体目标将是：(1)评估口服AMT治疗中重度斑块性银屑病的安全性；(2)建立口服AMT治疗中重度斑块型银屑病的量效关系；(3)使用PASI评分和安全性评估，确定是否将每周剂量分成两片，每12小时给药一次，而不是每周给药一次。根据2期研究结果，我们将选择口服AMT的剂量，以达到最大疗效和最佳反应时间，同时不会导致治疗出现的毒性或不耐受。然后，我们将把这一口服AMT剂量带入SBIR II期的3期双盲随机临床试验（390名受试者，每位受试者26周，30-36个月的入组期），通过以下具体目标来测试AMT与MTX的正面对比：(1)比较口服AMT和口服MTX治疗先前未接受过MTX的中重度斑块性银屑病患者的疗效；(2)通过比较不良事件和实验室参数，对AMT和MTX的安全性和耐受性进行比较，并对两种药物的神经认知和中枢神经系统相关副作用进行具体评估。主要疗效终点是第26周时PASI- n曲线下面积的改善，其中PASI- n是银屑病面积和严重程度指数（PASI）减少的平均百分比。次要疗效和神经认知终点包括：第10周和第26周达到PASI 50和PASI 75的受试者比例；时间到PASI 75 (Kaplan Meier)；医师整体评估（PGA）；皮肤病生活质量（DLQI）、银屑病症状评估（PSA）；以及MMSE、FACT - fatigue和FACT/GOG-Ntx的神经认知评分。在本文提出的2期和3期临床试验结束时，我们的目标是获得向FDA申请产品许可（NDA）所需的有效性和安全性数据，以便将AMT用于牛皮癣。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phase 2B trial of aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia.

氨基蝶呤多药治疗新诊断急性淋巴细胞白血病儿童的 2B 期试验。

DOI：
10.1007/s00280-007-0576-7
发表时间：
2008
期刊：
Cancer chemotherapy and pharmacology
影响因子：
3
作者：
Cole,PeterD;Drachtman,RichardA;Masterson,Margaret;Smith,AngelaK;Glod,John;Zebala,JohnA;Lisi,Stacey;Drapala,Drew-Anne;Kamen,BartonA
通讯作者：
Kamen,BartonA

A pilot open trial evaluating the efficacy of low-dose aminopterin in the canine homologue of human atopic dermatitis.

一项试点开放试验评估低剂量氨基蝶呤对人类特应性皮炎的犬同系物的功效。